CN101010325A - Process for the preparation of amino acids useful in the preparation of peptide receptor modulators - Google Patents

Process for the preparation of amino acids useful in the preparation of peptide receptor modulators Download PDF

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Publication number
CN101010325A
CN101010325A CNA2005800292225A CN200580029222A CN101010325A CN 101010325 A CN101010325 A CN 101010325A CN A2005800292225 A CNA2005800292225 A CN A2005800292225A CN 200580029222 A CN200580029222 A CN 200580029222A CN 101010325 A CN101010325 A CN 101010325A
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Prior art keywords
methyl ether
bromo
ethylbenzene
ethylbenzene methyl
receptor modulators
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A·马图尔
K·S·库马
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention provides process useful for the preparation of intermediates which are useful in the preparation of amino acids useful in preparing peptide receptor modulators, for example agonists or partial agonists of such peptide receptors. Such peptide receptor modulators include, for example glucagon like peptide-1 receptor modulators which are useful for the amelioration of the diabetic condition.

Description

Be used to prepare the amino acid whose preparation method of peptide receptor modulators
Invention field
The invention provides the intermediates preparation that can be used for synthesizing amino acid, described amino acid can be used for preparing the peptide receptor modulators, the agonist of for example above-mentioned peptide acceptor or partial agonist.This type of peptide receptor modulators comprises hyperglycemic-glycogenolytic factor, as helps improving the peptide-1 receptor regulator of diabetic conditions.
Background of invention
Wish exploitation peptide receptor modulators, be used to influence the natural radioactivity of above-mentioned acceptor and therefore influence the biological approach that contains above-mentioned acceptor.
For example, GLP-1 is a kind of important gastrointestinal hormone ` that has regulatory function in glucose metabolism and gastrointestinal secretion and metabolism, and has been confirmed as a kind of very strong and effective exciting agent that Regular Insulin discharges that is used for.Therefore, wish exploitation peptide acceptor (for example GLP-1 acceptor) conditioning agent, its natural radioactivity that will influence acceptor is to realize the biological response of expectation.
Therefore, the invention provides a kind of novel preparation method who is used for the intermediate of synthesizing amino acid, described amino acid can be used for preparing the peptide receptor modulators, and for example the GLP-1 receptor modulators comprises agonist or partial agonist.
Summary of the invention
In one aspect, the present invention relates to a kind of method that is used to prepare compound of Formula I:
Figure A20058002922200051
This method may further comprise the steps:
Methylate the 3-ethylphenol and generate 3-ethylbenzene methyl ether;
Bromination 3-ethylbenzene methyl ether in the contraposition of methoxyl group and generate 4-bromo-3-ethylbenzene methyl ether;
Transform 4-bromo-3-ethylbenzene methyl ether, described conversion comprises that (a) makes 4-bromo-3-ethylbenzene methyl ether and n-Butyl Lithium reaction to generate the lithium salts of 4-bromo-3-ethylbenzene methyl ether respective anionic; (b) the anionic lithium salts of 4-bromo-3-ethylbenzene methyl ether and triethyl borate are reacted; (c) use the aqueous acid cancellation.
In one aspect of the method, the present invention relates to a kind of method for preparing the compound of general formula I according to following scheme 1:
Figure A20058002922200061
Scheme 1
Figure A20058002922200062
In one aspect of the method, the present invention relates to a kind of method that is used to prepare general formula I I compound:
This method may further comprise the steps:
Methylate the 3-ethylphenol to generate 3-ethylbenzene methyl ether;
This 3-ethylbenzene methyl ether of bromination is to generate 4-bromo-3-ethylbenzene methyl ether in the contraposition of methoxyl group;
Transform 4-bromo-3-ethylbenzene methyl ether, described conversion comprises that (a) makes 4-bromo-3-ethylbenzene methyl ether and n-Butyl Lithium reaction to generate the lithium salts of 4-bromo-3-ethylbenzene methyl ether respective anionic; (b) the anionic lithium salts of 4-bromo-3-ethylbenzene methyl ether and tri-n-butyl borate are reacted; (c) use the aqueous acid cancellation;
In the presence of palladium catalyst, make resultant 2-ethyl-4-anisole ylboronic acid and the amino acid whose trifluoromethanesulfonic acid anhydride reactant of suitable protected tyrosine (Su Chuji coupling); With
Remove carboxyl-protecting group to obtain can be used for being attached to the amino protected amino acid the peptide receptor modulators from the benzidino-acid that generates.
In one aspect of the method, the present invention relates to a kind of method for preparing general formula I I compound according to following scheme 2:
Figure A20058002922200071
Scheme 2
Figure A20058002922200081
Embodiment
The present invention relates to be used for the intermediates preparation of synthesizing amino acid, described amino acid can be used for preparing the peptide receptor modulators, and for example the GLP-1 receptor modulators comprises agonist or partial agonist.
Above-mentioned peptide receptor modulators can be used for influencing the natural radioactivity of above-mentioned acceptor and therefore influences the biological approach that relates to above-mentioned acceptor.For example, GLP-1 is a kind of important gastrointestinal hormone ` that has regulatory function in glucose metabolism and gastrointestinal secretion and metabolism, and has been confirmed as a kind of very strong and effective stimulant that Regular Insulin discharges that is used for.
Method of the present invention can be used for preparing the compound of general formula I:
Figure A20058002922200082
It can be used for preparing the amino acid of general formula I I:
Figure A20058002922200091
The compound of general formula I I can be used for preparing the peptide receptor modulators.
Embodiment 1
Synthetic (2-ethyl-4-methoxyl group) phenyl-boron dihydroxide
Be prepared as follows (2-ethyl-4-methoxyl group) phenyl-boron dihydroxide (general formula I), and shown in scheme 1: (1) the 3-ethylphenol that methylates generates 3-ethylbenzene methyl ether; (2) bromination 3-ethylbenzene methyl ether generates 4-bromo-3-ethylbenzene methyl ether in the contraposition of methoxyl group; (3) transform 4-bromo-3-ethylbenzene methyl ether, conversion comprises that (a) generates 4-bromo-3-ethylbenzene methyl ether and n-Butyl Lithium reaction lithium salts of 4-bromo-3-ethylbenzene methyl ether respective anionic; (b) anionic lithium salts and the tri-n-butyl borate with 4-bromo-3-ethylbenzene methyl ether reacts; (c) use the aqueous acid cancellation.
Specifically, (98% is pure for 50g, 0.4mol, Fluka) and K for the 3-ethylphenol in anhydrous propanone (500ml) 2CO 3(283g, and mixture interpolation methyl iodide 2.05mol) (290g, 2.05mol).Reaction mixture transferred in the autoclave and 70 ℃ of backflows spend the night, make reaction mixture filtration over celite pad, use the acetone rinsing pad, concentrate the filtrate and the washing fluid that merge, product is dissolved among the DCM, filter evaporate to dryness.Yield: 50g, 90%, be brown liquid.
Room temperature in the dark stir 3-ethylbenzene methyl ether in the acetonitrile (1L) (50g, 0.3676mol) and N-bromosuccinimide (72g 0.4mol) reaches 8 hours.Be lower than 40 ℃ of concentrated reaction mixtures, the gained residuum is dissolved in CCl again 4In and filter concentrated filtrate and by the fractionation purified product.Yield: 35g, 43%, be light yellow liquid.
With the 4-bromo-3-ethylbenzene methyl ether in the tetrahydrofuran (THF) (900ml) (94g, 0.437mol) solution is cooled to-78 ℃, uniform temp drip down n-Butyl Lithium (249ml, 0.55mol).Continue to stir 1 hour at-78 ℃ ,-78 ℃ slowly add tri-n-butyl borates (177ml, 0.655mol).Remove cooling bath, with reaction mixture be warmed to 0 ℃ and 0 ℃ the time with the cancellation of 1.5N hydrochloric acid.Separate organic layer, use the ethyl acetate extraction water layer, the organic layer that merges with normal saline washing also concentrates.The gained residuum stirred in sherwood oil 30 minutes, filtered the gained solid and drying under vacuum.
Yield: 65g, 82%, be white solid.
Scheme 1
Figure A20058002922200101
Embodiment 2
Amino acid is synthetic
According to scheme 2, use institute's synthetic (2-ethyl-4-methoxyl group) phenyl-boron dihydroxide to prepare the amino acid of general formula I I:
Figure A20058002922200102
Scheme 2
Figure A20058002922200111
EXAMPLE III
The peptide receptor modulators is synthetic
The GLP-1 receptor modulators that can comprise general formula III by the peptide receptor modulators (EXAMPLE III) of the compound of general formula I I:
X aa1-X aa2-X aa3-X aa4-X aa5-X aa6-X aa7-X aa8-X aa9-X aa10-X aa11
III
Wherein
X Aa1Be hydrogen;
X Aa2Be Aib;
X Aa3Be E;
X Aa4Be G;
X Aa5Be T;
X Aa6Be L-α-Me-Phe (2-fluorine);
X Aa7Be T;
X Aa8Be S;
X Aa9Be D;
X Aa10It is the compound of general formula I I; With
X Aa11Be 4-(2 '-aminomethyl phenyl)-3-pyridyl L-Ala-NH 2
Wherein above-mentioned amino acid abbreviations is meant those of institute's common sense in the art.
The prepared peptide receptor modulators of intermediate by the inventive method preparation can be with the confessed prepared in any suitable way of chemistry of peptides those skilled in the art.For example, can on soluble polymer support (being also referred to as " resin "),, progressively synthesize peptide from the C-terminal of peptide.By formation acid amides or ester bond the C-terminal amino acid of peptide being attached to begins on the resin to synthesize.This makes the peptide that is generated finally discharge with the form of C-terminal acid amides or carboxylic acid respectively.If perhaps there is the C-terminal amino alcohol, as described herein, the C-terminal residue can be attached to 2-methoxyl group-4-alkoxy benzene methyl alcohol resin (SASRINTM, Bachem Bioscience, Inc., King ofPrussia, PA) on, and after finishing the peptide sequence assembling, with the LiBH among the THF 4The peptide alcohol that release is generated (see J.M.Stewart and J.D.Young, above-mentioned, the 92nd page).In addition, can use peptide synthesizer, for example the peptide synthesizer (ABI 433A) of the multiple peptide synthesizer (MPS396) of Advanced Chemtech or Applied Biosystems Inc..Can use following abbreviation in this article:
Ph=phenyl DCM=methylene dichloride
Bn=benzyl n-BuLi=just-butyllithium
I-Bu=isobutyl-Pd/C=palladium/carbon
I-Pr=sec.-propyl TEA=triethylamine
Me=methyl min=minute
Et=ethyl h or hr=hour
Pr=just-propyl group L=liter
Bu=just-butyl mL or ml=milliliter
TMS=trimethyl silyl μ L=microlitre
Et 2O=diethyl ether g=gram
HOAc or AcOH=acetate mg=milligram
MeCN=acetonitrile mol=mole
DMF=N, dinethylformamide mmol=mmole
EtOAc=ethyl acetate meq=milliequivalent
THF=tetrahydrofuran (THF) rt=room temperature
TFA=trifluoroacetic acid sat or sat ' d=are saturated
The NMP=N-methyl-2-pyrrolidone aq.=aqueous solution
LiBH 4=lithium borohydride mp=fusing point
DIEA=diisopropylethylamine Bip=biphenyl alanine
The FMOC=fluorenylmethyloxycarbonyl
Boc or BOC=tertbutyloxycarbonyl
The NBS=N-bromo-succinimide
The TLC=thin-layer chromatography
The HPLC=high performance liquid chromatography
LC/MS=high performance liquid chromatography/mass spectrum
MS or Mass Spec=mass spectrum
The NMR=nucleus magnetic resonance
The chemistry of peptides those skilled in the art know that amino-acid residue exists with the form of D and L isomer, present invention resides in any one or its mixture in the amino-acid residue isomer of introducing in peptide as described herein synthetic.
The present invention is not subjected to the restriction of described specific embodiment aspect scope, these embodiments are used for the independent illustrations of the individual aspect of the present invention.Except that shown in herein and described, book and accompanying drawing set out from the above description, and the method for function equivalent and component will become apparent for a person skilled in the art.Be intended in the scope that above-mentioned variant falls into claims.

Claims (4)

1, a kind of method that is used to prepare compound of Formula I,
Figure A2005800292220002C1
Said method comprising the steps of:
Methylate the 3-ethylphenol to generate 3-ethylbenzene methyl ether;
The described 3-ethylbenzene of bromination methyl ether is to generate 4-bromo-3-ethylbenzene methyl ether in the contraposition of methoxyl group;
Transform described 4-bromo-3-ethylbenzene methyl ether, described conversion comprises that (a) makes the lithium salts of described 4-bromo-3-ethylbenzene methyl ether and n-Butyl Lithium reaction with the respective anionic that generates described 4-bromo-3-ethylbenzene methyl ether; (b) the anionic described lithium salts of described 4-bromo-3-ethylbenzene methyl ether and tri-n-butyl borate are reacted; (c) use the aqueous acid cancellation.
2, a kind ofly prepare the method for compound of Formula I according to following scheme 1,
Figure A2005800292220002C2
Scheme 1
Figure A2005800292220002C3
3, a kind of method that is used to prepare general formula I I compound,
Figure A2005800292220003C1
Said method comprising the steps of:
Methylate the 3-ethylphenol to generate 3-ethylbenzene methyl ether;
The described 3-ethylbenzene of bromination methyl ether is to generate 4-bromo-3-ethylbenzene methyl ether in the contraposition of methoxyl group;
Transform described 4-bromo-3-ethylbenzene methyl ether, described conversion comprises that (a) makes the lithium salts of described 4-bromo-3-ethylbenzene methyl ether and n-Butyl Lithium reaction with the respective anionic that generates described 4-bromo-3-ethylbenzene methyl ether; (b) the anionic described lithium salts of described 4-bromo-3-ethylbenzene methyl ether and tri-n-butyl borate are reacted; (c) use the aqueous acid cancellation;
In the presence of palladium catalyst, make resultant 2-ethyl-4-anisole ylboronic acid and the amino acid whose trifluoromethanesulfonic acid anhydride reactant of suitable protected tyrosine (Su Chuji coupling); With
Remove carboxyl-protecting group to obtain can be used for being attached to the amino protected amino acid the peptide receptor modulators from the benzidino-acid that generates.
4, a kind ofly prepare the method for general formula I I compound according to following scheme 2,
Figure A2005800292220003C2
Scheme 2
Figure A2005800292220004C1
CNA2005800292225A 2004-07-02 2005-07-01 Process for the preparation of amino acids useful in the preparation of peptide receptor modulators Pending CN101010325A (en)

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